Photodynamic therapy for synovial hyperplasia in patients with refractory rheumatoid arthritis: a study protocol for a randomized, double-blind, blank-controlled prospective trial.

BACKGROUND: Persistent synovial hyperplasia with inflammation in rheumatoid arthritis is one of the main pathogeneses of refractory rheumatoid arthritis (RRA). Photodynamic therapy (PDT) causes less trauma than steroid injections or arthroscopic synovectomy while providing stronger targeting and more durable curative effects. The aim of this trial was to evaluate the short-, medium-, and long-term clinical efficacy of PDT when applied as a treatment for RRA synovial hyperplasia and synovitis. METHODS AND ANALYSIS: This protocol is for a single-center, randomized, double-blind, blank-controlled prospective trial. A sample of 126 RRA patients will be randomly divided into 3 groups: the control group, the "PDT once" group, and the "PDT twice" group, with 42 participants per group. The trial will be conducted by the Rheumatology and Immunology Department of the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University. The Ultrasound Compound Score of Synovitis (UCSS) has been selected as the primary outcome measure. The secondary outcome measures include knee joint clinical assessments, ratio of relapse, duration of remission, Disease Activity Score in 28 joints (DAS28), inflammation indexes, serum concentrations of specific antibodies, and changes in articular structures as detected by X-ray scans in the 48th week. The improvement ratios of the UCSS at the 8th, 24th, and 48th weeks (compared with baseline) reflect short-, medium-, and long-term time frames, respectively. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethics Committee of the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, China (Approval No. granted by the ethics committee: NFZXYEC-2017-005) and then entered in the Chinese Clinical Trials Registry under registration number ChiCTR1800014918 (approval date: February 21, 2018). All procedures are in accordance with Chinese laws and regulations and with the Declaration of Helsinki by the World Medical Association (WMA). Any modifications of this protocol during execution will need additional approval from the Ethics Committee of our hospital. TRIAL REGISTRATION NUMBER: ChiCTR1800014918 .

Streptomyces genisteinicus sp. nov., a novel genistein-producing actinomycete isolated from a Chinese medicinal plant and proposal of Streptomyces michiganensis Corbaz et al. 1957 as a later heterotypic synonym of Streptomyces xanthochromogenes Arishima et al. 1956.

A novel genistein-producing actinobacterial strain, designated strain CRPJ-33T, was isolated from the healthy leaves of a medicinal plant Xanthium sibiricum collected from Hunan Province, PR China. 16S rRNA gene sequence analysis indicated strain CRPJ-33T belonged to the genus Streptomyces and had 99.7, 99.0, 98.9, 98.9, 98.8 and 98.7% sequence similarities to Streptomyces zhihengii YIM T102T, Streptomyces eurocidicus NRRL B-1676T, Streptomyces xanthochromogenes NRRL B-5410T, Streptomyces michiganensis NBRC 12797T, Streptomyces mauvecolor LMG 20100T and Streptomyces lavendofoliae NBRC 12882T, respectively. Phylogenetic analysis of 16S rRNA gene sequences showed that strain CRPJ-33T was most closely related to S. zhihengii YIM T102T. However, digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) values between them were much less than the recommended threshold values. Furthermore, differential comparisons of the phenotypic characteristics were enough to distinguish strain CRPJ-33T from S. zhihengii YIM T102T. Meanwhile, the ANI and dDDH values or MLSA distances between strain CRPJ-33T and other type strains, which exhibited ≥98.7 % 16S rRNA gene sequence similarities to strain CRPJ-33T, were far away from the recommended threshold values. Based on these results, it is thought that strain CRPJ-33T should represent a novel species of the genus Streptomyces, for which the name Streptomyces genisteinicus sp. nov. is proposed. The type strain is CRPJ-33T (=MCCC 1K04965T=JCM 34526T). In addition, the phenotypic, chemotaxonomic and genotypic characteristics, as well as phylogenetic information revealed that the type strains of S. xanthochromogenes and S. michiganensis should belong to same genomic species. Consequently, it is proposed that S. michiganensis is a heterotypic synonym of S. xanthochromogenes for which an emended description is given.

A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression.

Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).

Steptomyces fagopyri sp. nov., a novel actinomycete isolated from rhizospheric soil of Fagopyrum dibotrys.

A novel actinomycete, designated strain QMT-28T, was isolated from rhizosphere soil of Fagopyrum dibotrys collected from Shuangfeng, Hunan Province, PR China. Strain QMT-28T grew well on International Streptomyces Project series media and formed well-developed, branched substrate hyphae and aerial mycelium that differentiated into loose spiral spore chains consisting of cylindrical spores with smooth surfaces. The diagnostic diamino acid was ll-diaminopimelic acid and the whole-cell sugars were galactose and glucose. The predominant fatty acids were C18 : 1 cis9, summed feature 6 (C18 : 2 cis 9,12/C18 : 0 a) and C16 : 0. The polar lipids included diphosphatidylglycerol, hydroxy phospatidylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides, phospholipids of unknown structure containing glucosamine and several unidentified phospholipids. The major menaquinones were MK-9, MK-9(H2), MK-9(H4), MK-9(H6) and MK-9(H8). The genome size of strain QMT-28T was about 8.7 Mbp with a G+C content of 71.2 mol%. Phylogenetic analysis showed that the novel strain was closely related to Streptomyces olivochromogenes DSM 40451T (99.5 % similarity), Streptomyces mirabilis NBRC 13450T (98.9 %), Streptomyces kanamyceticus NBRC 13414T (98.9 %), Streptomyces kaempferi I37T (98.9 %) and Streptomyces arcticus ZLN234T (98.8 %). However, the average nucleotide identity values, the digital DNA-DNA hybridization values and the multilocus sequence analysis evolutionary distances between this strain and closely related strains showed that it belonged to a distinct species. In addition, these results were also supported by differences in the phenotypic characteristics between QMT-28T and five closely related type strains. Consequently, strain QMT-28T should represent a novel species of the genus Streptomyces, with the suggested name Streptomyces fagopyri sp. nov. The type strain is QMT-28T (=CICC 24808T=JCM 33796T).

Streptomyces aquilus sp. nov., a novel actinomycete isolated from a Chinese medicinal plant.

The taxonomic position of a novel actinomycete isolate, designated strain GGCR-6T, isolated from the healthy leaves of Xanthium sibiricum collected from the botanic garden of Hunan University of Science and Technology in Hunan province, PR China, was determined by a polyphasic approach. GGCR-6T grew well on ISP series media and formed well-developed, branched substrate hyphae and aerial mycelium that differentiated into straight spore chains consisting of cylindrical spores with smooth surfaces. The diagnostic diamino acid was ll-diaminopimelic acid. The major menaquinones were MK-9(H8), MK-9(H2), MK-9 and MK-9(H6). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphotidylinositol and phosphatidylinositol mannosides. The predominant fatty acids were C16 : 1ω9c, iso-C16 : 0 and C16 : 0. The phenotypic characteristics of GGCR-6T indicated that it represented a member of the genus Streptomyces. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that GGCR-6T was most closely related to Streptomyces cyaneus NRRL B2296T and Streptomyces griseoruber NRRL B1818T. However, the digital DNA-DNA hybridization, the average nucleotide identity and the multi locus sequence analysis evolutionary distance clearly separate GGCR-6T from the phylogenetically closely related species. Furthermore, the novel isolate was distinctly differentiated from S. cyaneus NRRL B2296T and S. griseoruber NRRL B1818T by morphological, physiological and biochemical characteristics. Based on these data, strain GGCR-6T should be designated as a representative of a novel species of the genus Streptomyces, for which the name Streptomyces aquilus sp. nov. is proposed. The type strain is strain GGCR-6T (=CICC 11055T=JCM 33584T).

The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis.

Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641-0.928, I2  = 59.7%, Pheterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid.

[Effect of sanshui baihu decoction on the proliferation of fibroblast-like synoviocytes and its secretion of IL-6 and IL-17].

OBJECTIVE: To observe the effect of Sanshui Baihu Decoction (SBD) containing serum on the proliferation of in vitro cultured fibroblast-like synoviocytes (FLS) derived from rheumatoid arthritis (RA) and osteoarthritis (OA) and its secretion of interleukin-6 (IL-6) and IL-17, and to explore the pharmacological mechanism of SBD. METHODS: The FLS obtained from cultured RA and OA patients' synovial tissue were cultured and passaged in vitro in a routine way. The cultured medium was changed to DMEM with 20% SBD containing serum and cultured for 72 h after cultured for 3 to 6 generations. The proliferation rate of FLS was detected by MTT assay. Levels of IL-6 and IL-17 in the supernatant were detected by ELISA. Leflunomide and saline containing serum were used as positive and negative control respectively. RESULTS: SBD containing serum significantly inhibited the proliferation of RA-FLS and OA-FLS, and decreased the secretion of IL-17 in RA-FLS. Its inhibition efficiency of SBD was equivalent to that of Leflunomide. No obvious inhibition on the secretion of IL-6 in RA-FLS was observed. It had no significant effect on the secretion of IL-17 and IL-6 in OA-FLS. CONCLUSION: SBD could inhibit the proliferation of FLS and the secretion of IL-17 in RA-FLS, which might be one of its pharmacological mechanisms for treating RA.

Anti-inflammatory effect of Sanshuibaihu decoction may be associated with nuclear factor-kappa B and p38 MAPK alpha in collagen-induced arthritis in rat.

Sanshuibaihu decoction (SSBH) is an anti-arthritic Chinese herbal formula which has been used in the treatment of rheumatoid arthritis (RA) for many years. We herein aimed to confirm its anti-arthritic effect and explore the potential mechanism of action on collagen-induced arthritis (CIA) in rats. CIA was induced by immunizing 50 female Wistar rats with bovine type II collagen. 13 days following the immunization rats with CIA were treated with SSBH (50mg/kg), leflunomide (LEF) (10mg/kg) and physiological saline for 30 days, and rats without CIA were left untreated. After the treatment, paw edema was obviously improved in SSBH-treated rats, with the significant difference of arthritis score (F=6.032, P=0.006) observed between the three treated groups. In pathological observation, SSBH-treated rats showed a significant improvement of inflammatory infiltration, synovial hyperplasia, cartilage and bone destruction and joint fusion. After the treatment of SSBH, radiological score of knee (t=11.504, P=0.000) and ankle joints (t=9.250, P=0.000) was decreased significantly. In situ hybridization on joint tissue section indicated only slight synovial hyperblastosis and expression of NF-kappaB in SSBH-treated rats. Image analysis indicated a significant difference of means of integrated optical density (MIOD) (F=3.956, P=0.040) and means of stained area (MSA) (F=3.867, P=0.032) of NF-kappaB between the three treated groups. MIOD and MSA of SSBH-treated group were significantly lower vs control. Enzyme linked immunosorbent assay (ELISA) showed a significant difference (F=10.167, P=0.000) of the amount of p-p38 MAPKalpha in the three treated groups. The detected amount of p-p38 MAPKalpha in SSBH-treated group was significantly lower vs control. These results show SSBH has an inhibiting effect on CIA, which may be associated with NF-kappaB and p38 MAPKalpha.